6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders

ABSTRACT

The invention relates to novel pyrazolopyrimidinones according to formula (I): 
                         
wherein X, D, R a , R b , R c , R d , R e , m and n are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds and methods of using these compounds in the treatment of various diseases concerning deficits in perception, concentration, learning or memory.

The invention relates to novel pyrazolopyrimidinones according toformula (I)

whereby X is CR^(e) or unsubstituted N, D is optionally substitutedcyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl or 2-, 3-or 4-pyridyl, R^(a), R^(b), R^(c), R^(d), R^(e) are either H or optionalsubstituents, m=1 or 2 and n is 0, 1 or 2.

The new compounds are for use as active entities of medicaments or forthe manufacture of medicaments, in particular medicaments for thetreatment of conditions concerning deficits in perception,concentration, learning or memory. Such conditions may for example beassociated with Alzheimer's disease, schizophrenia and other diseases,in particular cognitive impairment associated with such diseases. Thecompounds of the invention show PDE9 inhibiting properties.

BACKGROUND OF THE INVENTION

The inhibition of phosphodiesterase 9A (PDE9A) is one of the currentconcepts to find new access paths to the treatment of cognitiveimpairments due to CNS disorders like Alzheimer's disease, schizophreniaand other diseases or due to any other neurodegenerative process of thebrain. With the present invention, new compounds that follow thisconcept are presented.

Phosphodiesterase 9A is one member of the wide family ofphosphodiesterases. These enzymes modulate the levels of the cyclicnucleotides 5′-3′ cyclic adenosine monophosphate (cAMP) and 5′-3′ cyclicguanosine monophosphate (cGMP). These cyclic nucleotides (cAMP and cGMP)are important second messengers and therefore play a central role incellular signal transduction cascades. Each of them reactivates interalia, but not exclusively, protein kinases. The protein kinase activatedby cAMP is called protein kinase A (PKA) and the protein kinaseactivated by cGMP is called protein kinase G (PKG). Activated PKA andPKG are able in turn to phosphorylate a number of cellular effectorproteins (e.g. ion channels, G-protein-coupled receptors, structuralproteins, transcription factors). It is possible in this way for thesecond messengers cAMP and cGMP to control a wide variety ofphysiological processes in a wide variety of organs. However, the cyclicnucleotides are also able to act directly on effector molecules. Thus,it is known, for example, that cGMP is able to act directly on ionchannels and thus is able to influence the cellular ion concentration(review in: Wei et al., Prog. Neurobiol., 1998, 56, 37-64). Thephosphodiesterases (PDE) are a control mechanism for the activity ofcAMP and cGMP and thus in turn for the corresponding physiologicalprocesses. PDEs hydrolyse the cyclic monophosphates to the inactivemonophosphates AMP and GMP. Currently, 11 PDE families have been definedon the basis of the sequence homology of the corresponding genes.Individual PDE genes within a family are differentiated by letters (e.g.PDE1A and PDE1B). If different splice variants within a gene also occur,then this is indicated by an additional numbering after the letters(e.g. PDE1A1).

Human PDE9A was cloned and sequenced in 1998. The amino acid identitywith other PDEs does not exceed 34% (PDE8A) and is never less than 28%(PDE5A). With a Michaelis-Menten constant (Km) of 170 nanomolar (nM),PDE9A has high affinity for cGMP. In addition, PDE9A is selective forcGMP (Km for cAMP=230 micromolar (μM)). PDE9A has no cGMP bindingdomain, suggesting that the enzyme activity is not regulated by cGMP. Itwas shown in a Western blot analysis that PDE9A is expressed in humansinter alia in testes, brain, small intestine, skeletal muscle, heart,lung, thymus and spleen. The highest expression was found in the brain,small intestine, kidney, prostate, colon and spleen (Fisher et al., J.Biol. Chem., 1998, 273 (25), 15559-15564; Wang et al., Gene, 2003, 314,15-27). The gene for human PDE9A is located on chromosome 21q22.3 andcomprises 21 exons. 4 alternative splice variants of PDE9A have beenidentified (Guipponi et al., Hum. Genet., 1998, 103, 386-392). ClassicalPDE inhibitors do not inhibit human PDE9A. Thus, IBMX, dipyridamole,SKF94120, rolipram and vinpocetine show no inhibition on the isolatedenzyme in concentrations of up to 100 micromolar (μM). An IC50 of 35micromolar (μM) has been demonstrated for zaprinast (Fisher et al., J.Biol. Chem., 1998, 273 (25), 15559-15564).

Murine PDE9A was cloned and sequenced in 1998 by Soderling et al. (J.Biol. Chem., 1998, 273 (19), 15553-15558). This has, like the humanform, high affinity for cGMP with a Km of 70 nanomolar (nM).Particularly high expression was found in the mouse kidney, brain, lungand liver. Murine PDE9A is not inhibited by IBMX in concentrations below200 micromolar either; the IC50 for zaprinast is 29 micromolar(Soderling et al., J. Biol. Chem., 1998, 273 (19), 15553-15558). It hasbeen found that PDE9A is strongly expressed in some regions of the ratbrain. These include olfactory bulb, hippocampus, cortex, basal gangliaand basal forebrain (Andreeva et al., J. Neurosci., 2001, 21 (22),9068-9076). The hippocampus, cortex and basal forebrain in particularplay an important role in learning and memory processes. As alreadymentioned above, PDE9A is distinguished by having particularly highaffinity for cGMP. PDE9A is therefore active even at low physiologicalconcentrations, in contrast to PDE2A (Km=10 micromolar (μM); Martins etal., J. Biol. Chem., 1982, 257, 1973-1979), PDE5A (Km=4 micromolar (μM);Francis et al., J. Biol. Chem., 1980, 255, 620-626), PDE6A (Km=17micromolar (μM); Gillespie and Beavo, J. Biol. Chem., 1988, 263 (17),8133-8141) and PDE11A (Km=0.52 micromolar (μM); Fawcett et al., Proc.Nat. Acad. Sci., 2000, 97 (7), 3702-3707). In contrast to PDE2A(Murashima et al., Biochemistry, 1990, 29, 5285-5292), the catalyticactivity of PDE9A is not increased by cGMP because it has no GAF domain(cGMP-binding domain via which the PDE activity is allostericallyincreased) (Beavo et al., Current Opinion in Cell Biology, 2000, 12,174-179). PDE9A inhibitors may therefore lead to an increase in thebaseline cGMP concentration.

This outline will make it evident that PDE9A engages in specificphysiological processes in a characteristic and unique manner, whichdistinguishes the role of PDE9A from any of the other PDE familymembers.

WO 2004/099210 discloses 6-arylmethyl-substituted pyrazolopyrimidinoneswhich are PDE9 inhibitors.

WO 2004/099211 discloses 6-cyclylmethyl- and 6-alkylmethyl-substitutedpyrazolopyrimidines and their use for the improvement of cognition,concentration etc.

DE 102 38 722 discloses the use of PDE9A-inhibitors for the improvementof cognition, concentration.

WO 2004/018474 discloses phenyl-substituted pyrazolopyrimidines andtheir use for the improvement of perception, concentration learningand/or memory.

WO 2004/026876 discloses alkyl-substituted pyrazolopyrimidines and theiruse for the improvement of awareness, concentration learning capacityand/or memory performance.

WO 2004/096811 discloses heterocyclic bicycles as PDE9 inhibitors forthe treatment of diabetes, including type 1 and type 2 diabetes,hyperglycemia, dyslipidemia, impaired glucose tolerance, metabolicsyndrome and/or cardiovascular disease.

WO2009068617 discloses PDE9 inhibiting compounds derived frompyrazolopyrimidinones with a substituted phenylmethyl- or pyridyl-methylgroup in the 6-position.

WO2010112437 discloses PDE9 inhibiting compounds derived frompyrazolopyrimidinones with a phenyl or heteroaryl substitutedarylmethyl- or heteroaryl-methyl group in the 6-position.

WO 2009/121919 discloses PDE9 inhibitors derived frompyrazolopyrimidinones with a non-aromatic heterocyclyl group in the1-position, among which is tetrahydropyranyl.

WO 2010/026214 discloses PDE9 inhibitors derived frompyrazolopyrimidinones with a cycloalkyl or a cycloalkenyl group in the1-position, among which is 4,4-difluorocyclohexyl.

Some references are directed to nucleoside derivatives. For example, WO2002/057425 discloses nucleoside derivatives which are inhibitors ofRNA-dependent RNA viral polymerase. WO 2001/060315 discloses nucleosidederivatives for the treatment of hepatitis C infection. EP679657discloses compounds that serve as ribonucleoside analogues. US2002058635discloses purine L-nucleoside compounds, in which both the purine ringsand the carbohydrate ring (pentose ring) are either modified,functionalized, or both, so the carbohydrate ring for example must showat least one esterified hydroxy group.

WO 2005/051944 discloses oxetane-containing nucleosides for thetreatment of nucleoside analogue related disorders such as disordersinvolving cellular proliferation and infection.

WO 2006/084281 discloses inhibitors of the E1 activation enzyme thathave a sulfonamide moiety.

WO 1998/40384 discloses pyrazolopyrimidinones which are PDE1, 2 and 5inhibitors and can be employed for the treatment of cardiovascular andcerebrovascular disorders and disorders of the urogenital system.

CH396 924, CH396 925, CH396 926, CH396 927, DE1147234 and DE1149013,describe pyrazolopyrimidines which have a coronary-dilating effect andwhich can be employed for the treatment of disturbances of myocardialblood flow.

U.S. Pat. No. 3,732,225 describes pyrazolopyrimidines which have ananti-inflammatory and blood glucose-lowering effect.

DE2408906 describes styrylpyrazolopyrimidinones which can be employed asantimicrobial and anti-inflammatory agents for the treatment of, forexample, oedema.

OBJECTIVE OF THE INVENTION

Changes in the substitution pattern of pyrazolopyrimidinones result ininteresting changes concerning biological activity and changes in theaffinity towards different target enzymes.

Therefore it is an objective of the present invention to providecompounds as herein described, in particular in the claims, thateffectively modulate PDE9A for the purpose of the development of amedicament, in particular in view of diseases or conditions, thetreatment of which are accessible via PDE9A modulation.

It is another objective of the present invention to provide compoundsthat are useful for the manufacture of a medicament for the treatment ofCNS disorders.

Yet another objective of the present invention is to provide compoundswhich show a favourable safety profile.

Another objective of the present invention is to provide compounds thathave a favourable selectively profile in favour for PDE9A inhibitionover other PDE family members and other pharmacological targets and bythis may provide advantage.

Yet another objective is to provide a medicament that may not only servefor treatment but might also be used for the prevention or modificationof the corresponding disease or condition.

The present invention further provides a pharmaceutical compositioncomprising a compound as herein described, in particular in the claims,and a pharmaceutically acceptable carrier.

The present invention further provides a method for the treatment of anyof the conditions as described herein in a mammal in need of suchtreatment, preferably a human, comprising administering to the mammal atherapeutically effective amount of a compound as herein described, inparticular in the claims.

The present invention further provides a compound as herein described,in particular in the claims, for use in a method of treatment of thehuman or animal body by therapy.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The compounds of the present invention are characterised by generalformula (I):

whereinX is N or CR^(e),R^(a), R^(b), R^(c), R^(e) are selected independently of each other fromthe group consisting of H, C₁₋₆-alkyl-, C₁₋₆-alkyl-O—, CF₃—, CHF₂—,CH₂F—, NC— and halogen;

-   -   whereby C₁₋₆-alkyl- and C₁₋₆-alkyl-O— optionally may be        substituted with haolgen, preferably with fluoro        R^(d): is selected from the group consisting of fluorine, NC—,        —CF₃, —CHF₂, —CH₂F, and methyl;        D: is selected from the group consisting of cyclopentyl,        cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and        4-pyridyl,    -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, NC—, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, NC—, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4        substituents, whereby said substituents may be selected        independently of one another from the group consisting of        fluorine, chlorine, bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—,        C₁₋₆-alkyl- and C₃₋₇-cycloalkyl;        m: is selected from 1 or 2, preferably 1;        n: is selected from 0, 1 or 2, preferably, 0 or 1, more        preferably 0,    -   whereby if n=2, the two groups R^(d) are selected independently        of one another;        and salts, preferably pharmaceutically acceptable salts thereof,        solvates thereof and the solvates of the aforementioned salts        thereof.

This embodiment is embodiment 1 of the present invention.

Embodiment 2 of the Present Invention

Another embodiment of the invention concerns a compound according togeneral formula (I), wherein

X is N or CR^(e),

R^(a), R^(b), R^(c), R^(e) are selected independently of each other fromthe group consisting of H, C₁₋₃-alkyl-, C₁₋₃-alkyl-O—, —CF₃, —CHF₂,—CH₂F, NC— and halogen;

-   -   whereby C₁₋₆-alkyl- and C₁₋₆-alkyl-O— optionally may be        substituted with halogen, preferably fluoro        R^(d): is selected from the group consisting of fluorine, NC—,        —CF₃, —CHF₂, —CH₂F and methyl;        D: is selected from the group consisting of cyclopentyl,        cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and        4-pyridyl,    -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;        m: is selected from 1 or 2, preferably m is 1;        n: is 0, 1 or 2, preferably n is 0 or 1, more preferably n is 0,    -   whereby if n=2, these two groups R^(d) are selected        independently of one another;        and salts, preferably pharmaceutically acceptable salts thereof,        solvates thereof and the solvates of the aforementioned salts        thereof.

Embodiment 3 of the Present Invention

Another embodiment of the invention concerns a compound according togeneral formula (I), wherein

X is N or CR^(e),

R^(a), R^(b), R^(c), R^(e) are selected independently of each other fromthe group consisting of H, methyl, ethyl, methoxy, ethoxy, —CF₃, —CHF₂,—CH₂F, NC— and halogen; preferably R^(a), R^(b), R^(c), R^(e) areselected independently from the group consisting of H, methyl, ethyl,methoxy, ethoxy, —CF₃ and NC—,D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;        m: is selected from 1 or 2, preferably m is 1;        n is 0,        and salts, preferably pharmaceutically acceptable salts thereof,        solvates thereof and the solvates of the aforementioned salts        thereof.

Embodiment 4 of the Present Invention

Another embodiment of the invention concerns a compound according togeneral formula (I), wherein

X is N or CR^(e),

R^(b), R^(c), R^(d), R^(e) are each H,

R_(a) is selected from the group consisting of H, methyl, ethyl,methoxy, ethoxy, —CF₃, —CHF₂, —CH₂F and F;

D: is selected from the group consisting of cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,

-   -   whereby cyclopentyl and cyclohexyl optionally may be substituted        by 1 or 2 substituents, whereby said substituents may be        selected independently of one another from the group consisting        of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby tetrahydrofuranyl and tetrahydropyranyl optionally may        be substituted by 1 or 2 substituents, whereby said substituents        may be selected independently of one another from the group        consisting of fluorine, F₃C—, HF₂C— and FH₂C—;    -   whereby pyridyl optionally may be substituted by 1, 2, 3 or 4,        preferably 1, 2 or 3, more preferably 1 or 2, substituents,        whereby said substituents may be selected independently of one        another from the group consisting of fluorine, chlorine,        bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- and        C₃₋₇-cycloalkyl;        m: is selected from 1 or 2, preferably m is 1;        n is 0,        and salts, preferably pharmaceutically acceptable salts thereof,        solvates thereof and the solvates of the aforementioned salts        thereof.

Embodiments 5 to 9 of the Present Invention

Other embodiments of the invention concern a compound according to eachof embodiments 1 to 4, wherein m is 1,

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Embodiments 10 to 18 of the Present Invention

Other embodiments of the invention concern a compound according to eachof embodiments 1 to 9, wherein

D is either 4,4-difluorocyclohexyl or tetrahydropyran-4-yl or4-methyl-3-pyridyl and none of these two groups has further substituentsand

m is 1.

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Embodiments 19 to 36 of the present invention concern a compoundaccording to each of embodiments 1 to 18, wherein X═N.

Embodiments 37 to 56 of the present invention concern a compoundaccording to each of embodiments 1 to 18, wherein X═CR^(e).

For all embodiments 1 to 56: the configuration of the cycloalkl group atposition 6 of the pyrazolopyrimidinones group with respect to saidpyrazolopyrimidinones group and the substituent R¹ may be cis or trans.

In this respect the compounds of the invention may have the followingconfigurations:

trans configuration 1  

formula (Ia) trans configuration 2  

formula (Ib) cis configuration 1  

formula (Ic) cis configuration 2  

formula (Id) whereby R^(a), R^(b), R^(c), R^(d), D, m and n are asdefined in any of the embodiments 1 to 56. m. These stereochemicallydefined embodiments are a further aspect of the invention.

Embodiment 57 of the Present Invention

Within the context of the present invention one or more compound(s) is(are) preferred that are selected from the group of specifically definedspecies as listed in the following table 1. These compounds representcompounds according to general formula (I) wherein X is N. The leftcolumn contains a letter code to identify the compound family, which isthe group of compounds that have the same general chemical structuralformula if no stereochemical properties are considered.

Table 1 of species: A

A a

A b

A c

A d

B

B a

B b

B c

B d

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Embodiment 58 of the Present Invention

Another embodiment of the present invention concerns one or morecompound(s) is (are) that are selected from the group of specificallydefined species as listed in the following table 2. These compoundsrepresent compounds according to general formula (I) wherein X is CR^(e)and R^(e) is H. The left column contains a letter code to identify thecompound family, which is the group of compounds that have the samegeneral chemical structural formula if no stereochemical properties areconsidered.

Table 2 of species: C

C a

C b

C c

C d

D

D a

D b

D c

D d

and salts, preferably pharmaceutically acceptable salts thereof,solvates thereof and the solvates of the aforementioned salts thereof.

Within the latter group of compounds according to tables 1 and 2 (i.e.embodiments 57 and 58), compounds that show trans configuration withrespect to the substitution at the cyclobutyl-group may be preferredover compounds with cis configuration. Of the possible trans configuredcompounds one may show advantages in efficacy. The more efficacious acompound, the more it is among the preferred compounds. Other criterionwhich may differentiate preferred compounds according to the inventionare the balance of efficacy and safety, and selectivity vs. other PDEfamily members such as PDE1C.

The different stereoisomers are subject to individual embodimentsaccording to the invention: For each of the embodiments 1 to 56:whenever D may be tetrahydrofuranyl, it is preferablytetrahydrofuran-3-yl; whenever D may be tetrahydropyranyl it ispreferable tetrahydropyran-3-yl or tetrahydropyran-4-yl, more preferablytetrahydropyran-4-yl.

TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by a person skilled in the art in light of thedisclosure and the context. Examples include that specific substituentsor atoms are presented with their 1 or 2 letter code, like H forhydrogen, N for nitrogen, C for carbon, O for oxygen, S for sulphur andthe like. Optionally but not mandatory the letter is followed orpreceeded by a hyphen to indicate a bond. As used in the specification,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆ alkylmeans an alkyl group or alkyl radical having 1 to 6 carbon atoms. Ingeneral, for groups comprising two or more subgroups, the last namedgroup is the radical attachment point, for example, “alkyl-O—” means amonovalent radical of the formula alkyl-O—, which is attached via theoxygen atom thereof (i.e. a alkoxy-substituent). If the term of asubstituent starts or ends with a minus sign or hyphen, i.e.—, this signemphasises the attachment point like in the aforementioned exampleAlkyl-O—, where the O is linked to the group of which the alkoxy-groupis a substituent. Unless otherwise specified below, conventionaldefinitions of terms control and conventional stable atom valences arepresumed and achieved in all formulas and groups.

In general, if terms are specifically defined with a given context, suchspecific definitions shall prevail over the more general definitions asoutlined in this paragraph.

In general, all “tautomeric forms and isomeric forms and mixtures”,whether individual geometric isomers or optical isomers or racemic ornon-racemic mixtures of isomers of a chemical structure or compound areintended, unless the specific stereochemistry or isomeric form isspecifically indicated in the compound name or structure. Specificdefinitions prevail.

“Substitution”: The term “substituted” as used herein explicitly orimplicitly, means that any one or more hydrogen(s) on the designatedatom is replaced with a member of the indicated group of substituents,provided that the designated atom's normal valence is not exceeded. Incase a substituent is bound via a double bond, e.g. an oxo substituent,such substituent replaces two hydrogen atoms on the designated atom. Thesubstitution shall result in a stable compound. “Stable” in this contextpreferably means a compound that from a pharmaceutical point of view ischemically and physically sufficiently stable in order to be used as anactive pharmaceutical ingredient of a pharmaceutical composition. If asubstituent is not defined, it shall be hydrogen. By the term“optionally substituted” is meant that either the corresponding group issubstituted or it is not. A characterisation that substituents of thesame group may be “selected independently of one another” shall meanthat the corresponding substituents may be the same or may be different.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

“pharmaceutically acceptable salt(s)” of the compounds according to theinvention are subject of the present invention as well. The term“pharmaceutically acceptable salt(s)” refers to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof, preferably addition salts. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues/parts of the compoundsof the present invention such as aminofunctions; acidic residues/partswithin compounds of the present invention may form salts with alkali ororganic bases. The pharmaceutically acceptable salts include theconventional non-toxic salts or the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and thelike; and the salts prepared from organic acids such as acetic acid,propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid,malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid,maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid,benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid,fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid and the like.

Physiologically acceptable salts with bases also may include salts withconventional bases such as, by way of example and preferably, alkalimetal salts (e.g. sodium and potassium salts), alkaline earth metalsalts (e.g. calcium and magnesium salts) and ammonia, organic amineshaving 1 to 16 C atoms, such as, by way of example and preferably,ethylamine, diethylamine, triethylamine, ethyldiisopropylamine,monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methyl-morpholine,dehydroabietylamine, arginine, lysine, ethylenediamine andmethylpiperidine and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound with basic or acidic properties byconventional chemical methods. Generally, such salts can be prepared byreacting the free acid or base form of these compounds with astoichiometric amount of the appropriate base or acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred.

A “Prodrug” is considered a compound that is designed to release abiologically active compound according to the present invention in-vivowhen such prodrug is administered to a mammalian subject. Prodrugs ofcompounds according to the present invention are prepared by modifyingfunctional groups present in the compound of the invention in such a waythat these modifications are retransformed to the original functionalgroups under physiological conditions. It will be appreciated thatprodrugs of the compounds according to the present inventions aresubject to the present invention as well.

“Metabolites” are considered derivatives of the compounds according tothe present invention that are formed in-vivo. Active metabolites aresuch metabolites that cause a pharmacological effect. It will beappreciated that metabolites of the compounds according to the presentinventions are subject to the present invention as well, in particularactive metabolites.

Some of the compounds may form “solvates”. For the purposes of theinvention the term “solvates” refers to those forms of the compoundswhich form, in the solid or liquid state, a complex by coordination withsolvent molecules. Hydrates are a specific form of solvates in which thecoordination takes place with water. According to the present invention,the term preferably is used for solid solvates, such as amorphous ormore preferably crystalline solvates.

“Scaffold”: The scaffold of the compounds according to the presentinvention is represented by the following core structure. The numerationof the positions of the ring member atoms is indicated in bold:

It will be evident for the skilled person in the art, that this scaffoldcan be described by its tautomeric “enol” form

In the context of the present invention both structural representationsof the scaffold shall be considered the subject of the presentinvention, even if only one of the two representatives is presented.Without meant to be limiting or bound, it is believed that for themajority of compounds under ambient conditions and therewith underconditions which are the relevant conditions for a pharmaceuticalcomposition comprising said compounds, the equilibrium of the tautomericforms lies on the side of the pyrazolopyrimdin-4-one representation.Therefore, all embodiments are presented aspyrazolopyrimdin-4-one-derivatives or more precisely aspyrazolo[3,4-d]pyrimidin-4-one derivatives.

“Bonds”: If within a chemical formula of a ring system or a definedgroup a substituent is directly linked to an atom or a group like “RyR”in the formula below, this shall mean that the substituent is onlyattached to the corresponding atom. If however from another substituentlike “RxR” a bond is not specifically linked to an atom of the ringsystem but drawn towards the centre of the ring or group this means thatthis substituent “RxR” may be linked to any meaningful atom of the ringsystem/group unless stated otherwise.

The bond symbol “−” (=minus sign) or the symbol “−*” (=minus signfollowed by an asterisk sign) stands for the bond through which asubstituent is bound to the corresponding remaining part of themolecule/scaffold. In cases in that the minus sign does not seem to besufficiently clear, there may be added an asterisk to the bond symbol“-” in order to determine the point of attachment of said bond with thecorresponding main part of the molecule/scaffold.

The term “C₁₋₆-alkyl” denotes a saturated, branched or unbranchedhydrocarbon group with 1 to 6 C atoms. Examples of such groups includemethyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl,iso-hexyl. This definition applies for the use of “alkyl” in anyreasonable context within the present description in the absence of afurther definition.

The term “C₃₋₇-cycloalkyl” denotes a saturated monocyclic group with 3to 7 C ring atoms. Preferred are 5 or 6 membered cycloalkyl-groups.There are no other ring atoms than carbon atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.This definition applies for “cycloalkyl” in any reasonable contextwithin the present description in the absence of a further definition.

The terms “halogen” stands for fluoro (F), chloro (Cl) and bromo (Br)substituents, preferably F and Cl and more preferably F.

The terms “pyridyl” defines a pyridine-substituent, sometimes alsocalled pyridinyl.

Expressions like “prevention”, “prophylaxis”, “prophylactic treatment”or “preventive treatment” used herein should be understood synonymousand in the sense that the risk to develop a condition mentionedhereinbefore is reduced, especially in a patient having elevated riskfor said conditions or a corresponding anamnesis. Thus the expression“prevention of a disease” as used herein means the management and careof an individual at risk of developing the disease prior to the clinicalonset of the disease. The purpose of prevention is to combat thedevelopment of the disease, condition or disorder and includes theadministration of the active compounds to prevent or delay the onset ofthe symptoms or complications and to prevent or delay the development ofrelated diseases, conditions or disorders. Success of said preventivetreatment is reflected statistically by reduced incidence of saidcondition within a patient population at risk for this condition incomparison to an equivalent patient population without preventivetreatment.

The expression “treatment” or “therapy” preferably means therapeutictreatment of (e.g. preferably human) patients having already developedone or more of said conditions in manifest, acute or chronic form,including symptomatic treatment in order to relieve symptoms of thespecific indication or causal treatment in order to reverse or partiallyreverse the condition or to delay the progression of the indication asfar as this may be possible, depending on the condition and the severitythereof. Thus the expression “treatment of a disease” as used hereinmeans the management and care of a patient having developed the disease,condition or disorder. The purpose of treatment is to combat thedisease, condition, disorder or a symptom thereof. Treatment includesthe administration of the active compounds to eliminate or control thedisease, condition or disorder as well as to alleviate the symptoms orcomplications associated with the disease, condition or disorder.

The following schemes shall illustrate generally how to manufacture thecompounds of the present invention by way of example. The abbreviatedsubstituents may be as defined for the embodiments of formula (I) if notdefined otherwise within the context of the schemes:

Scheme 1:

In a first step 2-ethoxymethylene-malononitrile is condensed withmono-substituted hydrazines by heating in an appropriate solvent likeethanol in the presence of a base (e.g. triethylamine) to form thecorresponding 5-amino-1H-pyrazole-4-carbonitriles. These compounds areconverted in a second step to the corresponding amides, e.g. bytreatment of an ethanolic solution with ammonia (25% in water) andhydrogen peroxide (35% in water). In a third step, heating withdicarboxylic acid diesters under basic conditions (e.g. sodium hydridein ethanol) followed by the addition of aqueous sodium hydroxide leadsto 4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl substitutedcarboxylic acids. Successive reaction with oxalylchloride,trimethylsilyldiazomethane and hydrochloric acid, followed by reactionwith the corresponding 2-aminopyridazine(s), or the corresponding2-amino-pyridine(s) respectively, leads to the final product(s).

Scheme 2:

The mono-substituted hydrazine derivatives, that are used in step 1 ofscheme 1 can be prepared by reductive amination of a ketone withhydrazinecarboxylic acid tert-butyl ester followed by a deprotectionstep as shown in scheme 4 for an D being cyclopentyl or cyclohexyl asdefined in general formula (I) [cf., for example, J. W. Timberlake etal., “Chemistry of Hydrazo-, Azo-and Azoxy Groups”; Patai, S., Ed.;1975, Chapter 4; S. C. Hung et al., Journal of Organic Chemistry 1981,46, 5413-5414].

Further information also can be found in:

-   -   WO 2004/099210 (in particular page 9, last paragraph to page 14,        line 8, incorporated by reference),    -   with respect to the general manufacture of compounds with D        being tetrahydropyranyl more information can be found in        WO2009/121919, particularly on page 120 to 125 and the        experimental part thereof (herewith incorporated by reference),    -   with respect to D being 4,4-difluorocyclohexyl more information        can be found in WO 2010/026214, particularly on page 59 to 63        and the experimental part thereof (herewith incorporated by        reference),    -   and in the experimental section (exemplary embodiments) of this        description.        Method of Treatment

The present invention refers to compounds, which are consideredeffective in the treatment of diseases. The compounds according to theinvention effectively inhibit phosphodiesterase 9A and show preferencein for PDE9A compared with other PDE family members. Therefore thecompounds are effective and selective inhibitors of PDE9A and can beused for the development of medicaments. Such medicaments shallpreferably be used for the treatment of diseases in which the inhibitionof PDE9A can result in a therapeutic, prophylactic or disease modifyingeffect. Preferably the medicaments shall be used to improve perception,concentration, cognition, learning or memory, in particular insituations/diseases/syndromes such as:

mild cognitive impairment, age-associated learning and memoryimpairments, age-associated memory losses, vascular dementia,craniocerebral trauma, stroke, dementia occurring after strokes (poststroke dementia), post-traumatic dementia, general concentrationimpairments, concentration impairments in children with learning andmemory problems, Alzheimer's disease, Lewy body dementia, dementia withdegeneration of the frontal lobes, including Picks syndrome, Parkinson'sdisease, progressive nuclear palsy, dementia with corticobasaldegeneration, amyotropic lateral sclerosis (ALS), Huntington's disease,multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia,HIV dementia, epilepsy, temporal lobe epilepsy, schizophrenia,schizophrenia (with dementia), Korsakoff s psychosis or cognitiveimpairment associated with depression or bipolar disorder.

Another aspect of the present invention concerns the treatment of adisease which is accessible by PDE9A modulation, in particular sleepdisorders like insomnia or narcolepsy, bipolar disorder, metabolicsyndrome, obesity, diabetes mellitus, including type 1 or type 2diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, or adisease of the testes, brain, small intestine, skeletal muscle, heart,lung, thymus or spleen.

Thus the medical aspect of the present invention can be summarised inthat it is considered that a compound according to formula (I) or (II)as herein defined, in particular the specifically defined speciescompounds is used as a medicament.

Such a medicament preferably is for the treatment of a CNS disease.

In an alternative use, the medicament is for the treatment of a CNSdisease, the treatment of which is accessible by the inhibition of PDE9.

In an alternative use, the medicament is for the treatment of a diseasethat is accessible by the inhibition of PDE9, specifically PDE9A.

In an alternative use, the medicament is for the treatment, ameliorationand/or prevention of cognitive impairment being related to perception,concentration, cognition, learning or memory, preferably if suchcongitive impairment is associated with a disease or condition asdescribed in this section.

In an alternative use, the medicament is for the treatment ameliorationand/or prevention of cognitive impairment being related toage-associated learning and memory impairments, age-associated memorylosses, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post stroke dementia), post-traumatic dementia,general concentration impairments, concentration impairments in childrenwith learning and memory problems, Alzheimer's disease, Lewy bodydementia, dementia with degeneration of the frontal lobes, includingPicks syndrome, Parkinson's disease, progressive nuclear palsy, dementiawith corticobasal degeneration, amyotropic lateral sclerosis (ALS),Huntington's disease, multiple sclerosis, thalamic degeneration,Creutzfeld-Jacob dementia, HIV dementia, epilepsy, temporal lobeepilepsy, schizophrenia (with dementia), Korsakoff's psychosis orcognitive impairment associated with depression or bipolar disorder.

In an alternative use, the medicament is for the treatment ofAlzheimer's disease, schizophrenia or cognitive impairemnt associatedwith Alzheimers's disease or associated with schizophrenia.

In an alternative use, the medicament is for the treatment of sleepdisorders, bipolar disorder, metabolic syndrome, obesity, diabetesmellitus, hyperglycemia, dyslipidemia, impaired glucose tolerance, or adisease of the testes, brain, small intestine, skeletal muscle, heart,lung, thymus or spleen.

In a further aspect of the invention, the present invention relates tothe method of treatment or prevention of a condition or disease selectedfrom the above listed groups of conditions and diseases, whereby themethod comprises the administration of a therapeutically effectiveamount of a compound according to the invention in a human being in needthereof.

Pharmaceutical Compositions

Medicaments for administration, which are also subject to the presentinvention, comprise a compound according to the present invention in atherapeutically effective amount and a pharmaceutical carrier. By“therapeutically effective amount” it is meant that if the medicament isapplied via the appropriate regimen adapted to the patient's condition,the amount of said compound of formula (I) will be sufficient toeffectively treat, to prevent or to decelerate the progression of thecorresponding disease, or otherwise to ameliorate the state of a patientsuffering from such a disease. It may be the case that the“therapeutically effective amount” in a mono-therapy will differ fromthe “therapeutically effective amount” in a combination therapy withanother medicament.

The dose range of the compounds of general formula (I) applicable perday may be usually from 0.1 to 5000 mg, preferably from 0.1 to 1000 mg,preferably from 2 to 500 mg, more preferably from 5 to 250 mg, mostpreferably from 10 to 100 mg. A dosage unit (e.g. a tablet) preferablymay contain between 2 and 250 mg, particularly preferably between 10 and100 mg of the compounds according to the invention.

The actual pharmaceutically effective amount or therapeutic dosage willdepend on factors known by those skilled in the art such as age, weight,gender or other condition of the patient, route of administration,severity of disease and the like.

The compounds according to the invention may be administered by oral,parenteral (intravenous, intramuscular etc.), intranasal, sublingual,inhalative, intrathecal, topical or rectal route. Suitable preparationsfor administering the compounds according to the present inventioninclude for example patches, tablets, capsules, pills, pellets, dragees,powders, troches, suppositories, liquid preparations such as solutions,suspensions, emulsions, drops, syrups, elixirs, or gaseous preparationssuch as aerosols, sprays and the like. The content of thepharmaceutically active compound(s) should be in the range from 0.05 to90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions may be prepared in the usual way, e.g. with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabiliserssuch as alkali metal salts of ethylene-diamine-tetra-acetic acid,optionally using emulsifiers and/or dispersants, while if water shall beused as diluent, for example, organic solvents may optionally be used assolubilisers or dissolving aids and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral use the tablets may contain, in addition to the carriersspecified, additives such as sodium citrate, calcium carbonate anddicalcium phosphate together with various additional substances such asstarch, preferably potato starch, gelatine and the like. Lubricants suchas magnesium stearate, sodium laurylsulphate and talc may also be usedto produce the tablets. In the case of aqueous suspensions the activesubstances may be combined with various flavour enhancers or colouringsin addition to the abovementioned excipients.

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated.

Combinations with Other Active Substances

In another aspect, the present invention relates to a combinationtherapy in which a compound according to the present invention isadministered together with another active compound. Accordingly, theinvention also refers to pharmaceutical formulations that provide such acombination of active ingredients, whereby one of which is a compound ofthe present invention. Such combinations may be fixed dose combinations(the active ingredients that are to be combined are subject of the samepharmaceutical formulation) or free dose combinations (activeingredients are in separate pharmaceutical formulations).

Consequently, a further aspect of the present invention refers to acombination of each of the compounds of the present invention,preferably at least one compound according to the present invention,with another active compound for example selected from the group ofbeta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretasemodulators; amyloid aggregation inhibitors such as e.g. alzhemed;directly or indirectly acting neuroprotective and/or disease-modifyingsubstances; anti-oxidants, such as e.g. vitamin E, ginko biloba orginkolide; anti-inflammatory substances, such as e.g. Cox inhibitors,NSAIDs additionally or exclusively having Aβ (Abeta) loweringproperties; HMG-CoA reductase inhibitors, such as statins; acetylcholineesterase inhibitors, such as donepezil, rivastigmine, tacrine,galantamine; NMDA receptor antagonists such as e.g. memantine; AMPAreceptor agonists; AMPA receptor positive modulators, AMPkines, glycinetransporter 1 inhibitors; monoamine receptor reuptake inhibitors;substances modulating the concentration or release of neurotransmitters;substances inducing the secretion of growth hormone such as ibutamorenmesylate and capromorelin; CB-1 receptor antagonists or inverseagonists; antibiotics such as minocyclin or rifampicin; PDE1, PDE2,PDE4, PDE5 and/or PDE10 inhibitors, GABAA receptor inverse agonists;GABAA alpha5 receptor inverse agonists; GABAA receptor antagonists;nicotinic receptor agonists or partial agonists or positive modulators;alpha4beta2 nicotinic receptor agonists or partial agonists or positivemodulators; alpha7 nicotinic receptor agonists or partial agonists;histamine receptor H3 antagonists; 5-HT4 receptor agonists or partialagonists; 5-HT6 receptor antagonists; alpha2-adrenoreceptor antagonists,calcium antagonists; muscarinic receptor M1 agonists or partial agonistsor positive modulators; muscarinic receptor M2 antagonists; muscarinicreceptor M4 antagonists; metabotropic glutamate receptor 5 positiveallosteric modulators; metabotropic glutamate receptor 2 antagonists,metabotropic glutamate receptor 2/3 agonists, metabotropic glutamatereceptor 2 positive allosteric modulators and other substances thatmodulate receptors or enzymes in a manner such that the efficacy and/orsafety of the compounds according to the invention is increased and/orunwanted side effects are reduced.

This invention further relates to pharmaceutical compositions containingone or more, preferably one active substance. At least one activesubstance is selected from the compounds according to the inventionand/or the corresponding salts thereof. Preferably the compositioncomprises only one such active compound. In case of more than one activecompound the other one can be selected from the aforementioned group ofcombination partners such as alzhemed, vitamin E, ginkolide, donepezil,rivastigmine, tacrine, galantamine, memantine, ibutamoren mesylate,capromorelin, minocyclin and/or rifampicin. Optionally the compositioncomprises further ingredients such as inert carriers and/or diluents.

The compounds according to the invention may also be used in combinationwith immunotherapies such as e.g. active immunisation with Abeta orparts thereof or passive immunisation with humanised anti-Abetaantibodies or antibody fragments for the treatment of the abovementioned diseases and conditions.

The compounds according to the invention also may be combined withDimebon.

The compounds according to the invention also may be combined withantidepressants like amitriptyline imipramine hydrochloride (TOFRANIL),imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN),doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL).

Or the compounds according to the invention also may be combined withserotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram(CELEXA, CIPRAMIL) escitalopram (LEXAPRO, CIPRALEX), clomipramine(ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine(PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX),indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline(ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine(EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine(PRISTIQ), brasofensme and tesofensine.

The combinations according to the present invention may be providedsimultaneously in one and the same dosage form, i.e. in form of acombination preparation, for example the two components may beincorporated in one tablet, e.g. in different layers of said tablet. Thecombination may be also provided separately, in form of a freecombination, i.e. the compounds of the present invention are provided inone dosage form and one or more of the above mentioned combinationpartners is provided in another dosage form. These two dosage forms maybe equal dosage forms, for example a co-administration of two tablets,one containing a therapeutically effective amount of the compound of thepresent invention and one containing a therapeutically effective amountof the above mentioned combination partner. It is also possible tocombine different administration forms, if desired. Any type of suitableadministration forms may be provided.

The compound according to the invention, or a physiologically acceptablesalt thereof, in combination with another active substance may be usedsimultaneously or at staggered times, but particularly close together intime. If administered simultaneously, the two active substances aregiven to the patient together; if administered at staggered times thetwo active substances are given to the patient successively within aperiod of less than or equal to 12, particularly less than or equal to 6hours.

The dosage or administration forms are not limited. In the context ofthe present invention any suitable dosage form may be used. For example,the dosage forms may be selected from solid preparations such aspatches, tablets, capsules, pills, pellets, dragees, powders, troches,suppositories, liquid preparations such as solutions, suspensions,emulsions, drops, syrups, elixirs, or gaseous preparations such asaerosols, sprays and the like.

The dosage forms are advantageously formulated in dosage units, eachdosage unit being adapted to supply a single dose of each activecomponent being present. Depending from the administration route anddosage form the ingredients are selected accordingly.

The dosage for the above-mentioned combination partners may beexpediently ⅕ of the normally recommended lowest dose up to 1/1 of thenormally recommended dose.

The dosage forms are administered to the patient for example 1, 2, 3, or4 times daily depending on the nature of the formulation. In case ofretarding or extended release formulations or other pharmaceuticalformulations, the same may be applied differently (e.g. once weekly ormonthly etc.). It is preferred that the compounds of the invention beadministered either three or fewer times, more preferably once or twicedaily.

EXAMPLES Pharmaceutical Compositions

Examples which might illustrate possible pharmaceutical formulations,without being meant to be limiting:

The term “active substance” denotes one or more compounds according tothe invention including the salts thereof. In the case of one of theaforementioned combinations with one or more other active substances theterm “active substance” may also include the additional activesubstances.

Example A Tablets Containing 100 Mg of Active Substance

Composition: tablet

active substance 100.0 mg lactose  80.0 mg corn starch  34.0 mgpolyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg 220.0 mg

Example B Tablets Containing 150 Mg of Active Substance

Composition: Tablet

active substance 150.0 mg  powdered lactose 89.0 mg corn starch 40.0 mgcolloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg 

Example C Hard Gelatine Capsules Containing 150 Mg of Active Substance

active substance 150.0 mg lactose  87.0 mg corn starch (dried)  80.0 mgmagnesium stearate  3.0 mg 320.0 mg

Example D

Composition: Suppository

active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan 840.0 mgmonostearate 2000.0 mg 

Example E

Composition: Ampoules Containing 10 Mg Active Substance

active substance 10.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 2.0 mL

Example F

Composition: ampoules containing 50 mg of active substance

active substance 50.0 mg 0.01N hydrochloric acid q.s. double-distilledwater ad 10.0 mL

The preparation of any the above mentioned formulations can be donefollowing standard procedures.

Biological Assay

The in-vitro effect of the compounds of the invention can be shown withthe following biological assays.

PDE9A2 Assay Protocol:

The PDE9A2 enzymatic activity assay was run as scintillation proximityassay (SPA), in general according to the protocol of the manufacturer(GE Healthcare, former Amersham Biosciences, product number: TRKQ 7100).

As enzyme source, lysate (PBS with 1% Triton X-100 supplemented withprotease inhibitors, cell debris removed by centrifugation at 13.000 rpmfor 30 mM) of SF 9 cell expressing the human PDE9A2 was used. The totalprotein amount included in the assay varied upon infection andproduction efficacy of the SF9 cells and lay in the range of 0.1-100 ng.

In general, the assay conditions were as follows:

-   -   total assay volume: 40 microliter    -   protein amount: 0.1-50 ng    -   substrate concentration (cGMP): 20 nanomolar; ˜1 mCi/1    -   incubation time: 60 mM at room temperature    -   final DMSO concentration: 0.2-1%

The assays were run in 384-well format. The test reagents as well as theenzyme and the substrate were diluted in assay buffer. The assay buffercontained 50 mM Tris, 8.3 mM MgCl₂, 1.7 mM EGTA, 0.1% BSA, 0.05% Tween20; the pH of assay buffer was adjusted to 7.5. The reaction was stoppedby applying a PDE9 specific inhibitor (e.g. compounds according to WO2004/099210 or WO 2004/099211, like one of the enantiomers of example37, e.g.1-(2-Chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methyl-propyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one)in excess.

REFERENCES

-   Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M.    Characterization of the first potent and selective PDE9 inhibitor    using a cGMP reporter cell line. Molecular Pharmacology. 2005    December; 68(6):1775-81.-   van der Staay F J, Rutten K, Bärfacker L, Devry J, Erb C, Heckroth    H, Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J,    Reymann K G, Schröder U H, Hendrix M. The novel selective PDE9    inhibitor BAY 73-6691 improves learning and memory in rodents.    Neuropharmacology. 2008 October; 55(5):908-18.    PDE1C Assay Protocol:

The assay was run in an analogous manner to the PDE9A2 assay, with thefollowing differences: instead of PDE9A2 PDE1C has been used and theassay buffer contained in addition 50 nM Calmodulin, 3 mM CaCl₂. Thereaction can be stopped by applying the same inhibitor as the one thatis outlined above(1-(2-Chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methyl-propyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one).

Determination of IC₅₀:

IC₅₀ can be calculated with GraphPadPrism or other suitable softwaresetting the positive control as 100 and the negative control as 0. Forcalculation of IC₅₀, dilutions of the test compounds (substrates) areselected and tested following the aforementioned protocol.

Data

In the following IC₅₀ values for PDE9A2 inhibition [nanomolar (nM)]illustrate that the compounds according to the present invention inhibitPDE9, specifically PDE9A2. This shows that the compounds provide usefulpharmacological properties. The examples are not meant to be limiting.

The table also provides selectivity values (Selectivity) that show apreference of the compounds for PDE9A versus PDE1C. Selectivity is theratio (IC₅₀ for PDE1C inhibition [nanomolar (nM)])/(IC₅₀ for PDE9A2inhibition [nanomolar (nM)]).

The example numbers refer to the final examples as outlined in thesection Exemplary embodiments.

All data can be measured according to the procedure described herein.The definition enantiomer 1 or enantiomer 2 is refers to the elutionorders of enantiomers in chiral SFC and chiral HPLC.

Compound IC₅₀ PDE9A2 family Example No. [nanomolar] Selectivity A 1* 1288 A 2 (trans enantiomer 1) 0.5 532 A 3 (trans enantiomer 2) 19 85 C 4*6 123 D 5* 10 40 *trans racemic mixture

In-Vivo Effect:

It is believed that the positive in-vitro efficacy results of thecompounds of the present invention translate in positive in-vivoefficacy.

The in-vivo effects of the compounds of this invention can be tested inthe Novel Object Recognition test according to the procedure ofPrickaerts et al. (Neuroscience 2002, 113, 351-361), the socialrecognition test or the T-maze spontaneous alternation test according tothe procedures described by van der Staay et al. (Neuropharmacology2008, 55, 908-918). For further information concerning biologicaltesting one is also referred to these two citations.

Besides the inhibition property toward the target PDE9, compoundsaccording to the present invention may provide further advantageouspharmacokinetic properties.

For example, compounds according to the invention may show one or moreadvantages in the area of safety, balanced metabolism, low risk ofcausing drug—drug interaction and/or balanced clearance.

Compounds also might show one or more additional or alternativeadvantages in the area of bioavailability, high fraction absorbed, bloodbrain transport properties, a favourable (e.g. high mean) residence time(mrt), favourable exposure in the effect compartment and so on.

CHEMICAL MANUFACTURE Abbreviations

-   APCI Atmospheric pressure chemical ionization-   ACN acetonitrile-   DCM dichloromethane-   DEA diethylamine-   DIPEA diisopropylethylamine-   DME 1,2-dimethoxyethane-   DMF dimethylformamide-   EI electronic impact-   ESI electrospray ionization (in MS)-   EtOH ethanol-   Exp. Example-   GC-MS gas chromatography with mass spectrometric detection-   h hour(s)-   HPLC high performance liquid chromatography-   HPLC-MS coupled high performance liquid chromatography-mass    spectrometry-   M molar (mol/L)-   MeOH methanol-   min minutes-   MS mass spectrometry-   NMP 1-methyl-2-pyrrolidinone-   R_(t) retention time (in HPLC)-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin-layer chromatography-   HPLC ultra performance liquid chromatography    HPLC-MS Methods:    Method 1 (NH₄COOH)

Instrument: LC/MS Waters Acquity HPLC System DAD, SQD single quadrupole.Column: BEH C18 1.7 μm, 2.1 mm×50 mm; eluent A: water+ammonium formate 5mM+10% acetonitrile; eluent B: acetonitrile; gradient: A 100%, then to B100% in 1.20 min for 0.25 min; flow rate: 0.7 mL/min; UV detection: 254nm; ion source: ESI.

LC-MS Methods:

Method 1

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: WatersAlliance 2695, Waters 2996 diode array detector; column: VarianMicrosorb 100 C18, 30×4.6 mm, 3.0 μm; eluent A: water+0.13% TFA, eluentB: ACN; gradient: 0.0 min 5% B→0.18 min 5% B→2.0 min 98% B→2.2 min 98%B→2.3 min 5% B→2.5 min 5% B; flow rate: 3.5 mL/min; UV detection:210-380 nmMethod 1E Hydro

Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole;column: Synergi Hydro-RP80A, 4 um, 4.60×100 mm; eluent A: 90% water+10%acetonitrile+ammonium formate 10 mM; eluent B=ACN 90%+10% H₂O+NH₄COOH 10mM; gradient: A(100) for 1.5 min, then to B (100) in 10 min for 1.5 min;flow rate: 1.2 mL/min; UV Detection: 254 nm; Ion source: APCI.

Method 3

MS apparatus type: Waters Micromass ZQ; HPLC apparatus type: WatersAlliance 2695, Waters 2996 diode array detector; column: VarianMicrosorb C18, 20×4.6 mm, 5.0 μm; eluent A: water+0.15 TFA, eluent B:MeOH; gradient: 0.0 min 5% B→0.25 min 5% B→1.90 min 100% B→2.05 min 100%B→2.15 min 5% B→2.25 min 5% B; flow rate: 5.2 mL/min; UV detection:210-400 nm.

GC/MS Methods

Method 3A.2

Instrument: GC/MS Finnigan Thermo Scientific. Trace GC Ultra, DSQ IIsingle quadrupole. Column: DB-5MS, 25 m×0.25 mm×0.25 μm; carrier gas:helium, 1 mL/min constant flow; oven program: 50° C. (hold 1 minute), to100° C. in 10° C./min, to 200° C. in 20° C./min, to 300° C. in 30°C./min eluent, detection: trace DSQ II, single quadrupole; ion source:EI. Scan range: 50-450 a

Chiral HPLC Methods:

Chiral Method 1:

HPLC apparatus type: Agilent 1100; column: Daicel chiralcel OJ-H, 250mm×4.6 mm, 5.0 μm; eluent: hexane/EtOH 80:20; flow rate: 1 mL/min,Temperature: 25° C.; UV Detection: variable (200-500 nm).

Microwave Heating:

-   -   Discover® CEM instruments, equipped with 10 and 35 mL vessels.        General Comment Concerning the Presentation of the Structures

Some compounds have stereogenic centre(s). The structures depicted inthe experimental section, below, will not necessarily show all thepossible stereochemical possibilities of the compounds but only one.However, in such cases a term like “trans-racemic mixture” or“cis-racemic mixture” is added next to the depicted structure in orderto indicate the other stereochemical options.

An example is given below. The presented structural formula is

The added term “trans-racemic mixture” points to the secondstereochemical option:

Thus, the manufactured compound is a mixture of

This principle applies to other depicted structures as well.

Example 1A Cis-Racemic Mixture

2.00 g (13.9 mmol) cis-cyclobutan-1,2-dicarboxylic acid were mixed with15.5 mL EtOH at 0° C. and 2.15 mL (29.5 mmol) thionylchloride wereslowly added. The mixture was allowed to warm to room temperature andstirred for 2 h. The solvent was removed under reduced pressure and theproduct was filtered through a pad of activated basic alumina that wasafterwards washed with DCM. 2.70 g of the product were obtained.

GC (Method 3A.2): R_(t): 8.42 min

MS (EI): m/z: 155 (M-45)⁺,127 (M-73)⁺

The following example was synthesized in analogy to the preparation ofExample 1A, using the corresponding diacid as starting material.

MS Example Structure starting material R_(t) [min] (ESI pos, m/z) Exp.1B trans-racemic mixture

1.34 (Method 1) 201 (M + H)⁺

Example 2A Trans-Racemic Mixture

1.17 g (5.5 mmol)5-Amino-1-(tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid amideamide (see PCT patent application WO 09-121919) was mixed with 15 mL ofanhydrous EtOH, 2.7 g (13.8 mmol) of Example 1A and 0.89 g (22.2 mmol)of sodium hydride (60% suspension in mineral oil) were added. Thereaction mixture was heated to 140° C. for 40 min in a microwave oven(Power: 150 W). The mixture was cooled to room temperature, the solventwas removed under reduced pressure and the residue taken up with CitricAcid (5 ml of 10% solution in water); DCM was added and the organicphase was separated through a phase separator cartridge. The crudeobtained after evaporation of solvents (2.18 g) was purified byflash-chromatography [Eluent: (DCM/MeOH/AcOH 90:10:1)/DCM] starting withDCM and eluting the final product with a 1/1 ratio of the abovedescribed eluent. 1.14 g (64%) of the product were obtained.

UPLC-MS (Method 1): R_(t)=0.54

MS (ESI pos): m/z=319 (M+H)⁺

Example 3A Trans-Racemic Mixture

0.50 g (1.76 mmol) of Example 2A were dissolved in THF (5 ml) underinert atmosphere; the temperature was lowered at 0° C. before theaddition of DMF (1 drop) and oxalyl chloride (0.167 ml, 1.94 mmol). Thereaction mixture was stirred 2 h at 0° C. and afterwardstrimethylsilyldiazomethane (2M solution in diethyl ether) was added(1.76 ml; 3.52 mmol). After 2 h hydrochloric acid (4M solution indioxane) was added (0.88 ml; 3.52 mmol) and the temperature increased toroom temperature. The mixture was diluted with DCM and washed withNaHCO₃ saturated solution; the aqueous phase was extracted with DCM. Theorganic phases were collected and washed with NaCl saturated solution;the organic phase was dried and the residue obtained after evaporationof solvents (0.54 g) was used as such in the next steps.

UPLC-MS (Method 1): R_(t)=0.82

MS (ESI pos): m/z=351, 353 (M+H)⁺

Example 4A Trans-Racemic Mixture

1.00 g (4.09 mmol)5-Amino-1-(4,4-difluoro-cyclohexyl)-1H-pyrazole-4-carboxylic acid amide(see PCT patent application WO 2010/026214, example 8A) was mixed with15 mL of anhydrous EtOH, 2.46 g (12.3 mmol) of Example 1B and 0.66 g(16.4 mmol) of sodium hydride (60% suspension in mineral oil) wereadded. The reaction mixture was heated to 140° C. for 30 min in amicrowave oven. The mixture was cooled to room temperature and sodiumhydroxide solution (4 M aqueous solution) was added. The solvent wasremoved under reduced pressure. The residue was purified by preparativeHPLC (eluent A: water+0.13% TFA, eluent B: MeOH). 0.70 g (49%) of theproduct were obtained.

HPLC-MS (Method 1): R_(t)=1.24 min

MS (ESI pos): m/z=353 (M+H)⁺

Example 5A Trans-Racemic Mixture

0.250 g (0.71 mmol) of Example 4A were mixed with 2 mL THF. The mixturewas cooled with an ice bath and 0.060 mL (0.71 mmol) oxalylchloride andone drop of DMF were added. The reaction mixture was stirred at 0° C.for 1 h. To the reaction mixture were added 4 mL ACN and 0.710 mLtrimethylsilyldiazomethane (2.0 M in hexane, 1.42 mmol). The mixture wasstirred at 0° C. for 2 h, then 0.355 mL HCl (4.0 M in dioxane) wasslowly added. The reaction was stirred for 15 min. To the mixture wereadded ethylacetate and saturated sodium hydrogen carbonate solution. Theorganic layer was washed with water and brine and partially evaporated.The product was used for the next reaction without further purification.

HPLC-MS (Method 1): R_(t)=1.40 min

MS (ESI pos): m/z=385/387 (Cl).

Exemplary Embodiments Example 1 Trans-Racemic Mixture

Example 3A (1 g, 2.85 mmol) was suspended in dimethoxyethane in a 50 mlSchlenk tube; 3-amino-6-methylpyridazine was added; the Schlenk tube wasclosed with a stopper and the reaction mixture heated at 95° C. during14 h.

The temperature was lowered, the solvent was removed under reducedpressure and the crude passed through a SPE “STRATA” 10 g SCX cartridgeeluting with MeOH and afterwards with a NH₃ solution in MeOH; theobtained residue was purified by flash chromatography [EluentS:Cyclohexane/EtOAc (from 1/1 to 100% EtOAc), then EtOAc/MeOH (9/1)],yielding 0.69 g (59%) of the title compound.

HPLC-MS (Method 1Eh): R_(t)=7.62

MS (APCI): m/z=406 (M+H)⁺

The enantiomers of Example 1 were separated by semipreparative chiralHPLC.

Method for semipreparative enantioseparation:

Semipreprative conditions:

HPLC semipreparative system: Waters 600 pump; column: Daicel chiralcelOJ-H, 5.0 μm, 250 mm×20 mm; eluent: hexane/EtOH 80:20; flow rate: 15mL/min, Temperature: 25° C.; UV Detection: 230 nm

Example Structure R_(t) [min] Exp. 2 trans- enantiomer 1

14.84 (Chiral Method 1) Exp. 3 trans- enantiomer 2

17.51 (Chiral Method 1)

Example 4 Trans-Racemic Mixture

To Example 5A (crude product synthesized from 0.250 g (0.71 mmol) ofExample 4A) was added dropwise 0.118 g (1.24 mmol) pyridin-2-ylamine in4 mL EtOH. The reaction mixture was stirred overnight. The EtOH wasevaporated and the residue was mixed with 2 ml DMF and heated to 50° C.for 2 h. The residue was purified by preparative HPLC (eluent A:water+0.13% TFA, eluent B: MeOH). After freeze drying the residue wasdiluted with 2 ml 10% aqueous K₂CO₃ and extracted with DCM. Evaporationof the solvent and freeze drying from ACN/water yielded 44 mg of theproduct.

HPLC-MS: (Method 3): R_(t)=1.20 min; MS (ESI pos): m/z=425 (M+H)⁺

The following example was synthesized in analogy to the preparation ofExample 4, using the corresponding amine as starting material.

starting material: MS Example structure amine Rt [min] (ESI pos, m/z)Exp. 5 trans- racemic mixture

4-chlor-pyridin-2- ylamine 1.21 (Method 3) 459/61 (Cl) (M + H)⁺

The invention claimed is:
 1. A compound of formula (I)

wherein X is N or CR^(e), R^(a), R^(b), R^(c) and R^(e) are selectedindependently of each other from the group consisting of H, C₁₋₆-alkyl-,C₁₋₆-alkyl-O—, —CF₃, —CHF₂, —CH₂F, NC— and halogen; whereby C₁₋₆-alkyl-and C₁₋₆-alkyl-O— optionally may be substituted with halogen, R^(d): isselected from the group consisting of fluorine, NC—, —CF₃, —CHF₂, —CH₂Fand methyl; D: is selected from the group consisting of cyclopentyl,cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or2 substituents, whereby said substituents may be selected independentlyof one another from the group consisting of fluorine, NC—, F₃C—, HF₂C—and FH₂C—; whereby tetrahydrofuranyl and tetrahydropyranyl optionallymay be substituted by 1 or 2 substituents, whereby said substituents maybe selected independently of one another from the group consisting offluorine, NC—, F₃C—, HF₂C— and FH₂C—; whereby pyridyl optionally may besubstituted by 1, 2, 3 or 4 substituents, whereby said substituents maybe selected independently of one another from the group consisting offluorine, chlorine, bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—,C₁₋₆-alkyl- and C₃₋₇-cycloalkyl; m: is selected from 1 or 2; n: isselected from 0, 1 or 2, whereby if n=2, the two groups R^(d) areselected independently of one another; and salts thereof, solvatesthereof and the solvates of the aforementioned salts thereof.
 2. Acompound according to claim 1, wherein X is N or CR^(e), R^(a), R^(b),R^(c) and R^(e) are selected independently of each other from the groupconsisting of H, C₁₋₃-alkyl-, C₁₋₃-alkyl-O—, —CF₃, —CHF₂, —CH₂F, NC— andhalogen; whereby C₁₋₃alkyl- and C₁₋₃alkyl-O— optionally may besubstituted with halogen, R^(d): is selected from the group consistingof fluorine, NC—, —CF₃, —CHF₂, —CH₂F and methyl; D: is selected from thegroup consisting of cyclopentyl, cyclohexyl, tetrahydrofuranyl,tetrahydropyranyl, 2-, 3- and 4-pyridyl, whereby cyclopentyl andcyclohexyl optionally may be substituted by 1 or 2 substituents, wherebysaid substituents may be selected independently of one another from thegroup consisting of fluorine, F₃C—, HF₂C— and FH₂C—; wherebytetrahydrofuranyl and tetrahydropyranyl optionally may be substituted by1 or 2 substituents, whereby said substituents may be selectedindependently of one another from the group consisting of fluorine,F₃C—, HF₂C— and FH₂C—; whereby pyridyl optionally may be substituted by1, 2, 3 or 4 substituents, whereby said substituents may be selectedindependently of one another from the group consisting of fluorine,chlorine, bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—, C₁₋₆-alkyl- andC₃₋₇-cycloalkyl; m: is selected from 1 or 2; n: is selected from thegroup consisting 0, 1 or 2, whereby if n=2, the two groups R^(d) areselected independently of one another; and salts thereof, solvatesthereof and the solvates of the aforementioned salts thereof.
 3. Acompound according to claim 2, wherein X is N or CR^(e), R^(a), R^(b),R^(c) and R^(e) are selected independently of each other from the groupconsisting of H, methyl, ethyl, methoxy, ethoxy, CF₃—, —CHF₂, —CH₂F, NC—and halogen; D: is selected from the group consisting of cyclopentyl,cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or2 substituents, whereby said substituents may be selected independentlyof one another from the group consisting of fluorine, F₃C—, HF₂C— andFH₂C—; whereby tetrahydrofuranyl and tetrahydropyranyl optionally may besubstituted by 1 or 2 substituents, whereby said substituents may beselected independently of one another from the group consisting offluorine, F₃C—, HF₂C— and FH₂C—; whereby pyridyl optionally may besubstituted by 1, 2, 3 or 4 substituents, whereby said substituents maybe selected independently of one another from the group consisting offluorine, chlorine, bromine, NC—, F₃C—, HF₂C—, FH₂C—, F₃C—CH₂—,C₁₋₆-alkyl- and C₃₋₇-cycloalkyl; m: is selected from 1 or 2; n is 0, andsalts thereof, solvates thereof and the solvates of the aforementionedsalts thereof.
 4. A compound according to claim 1, wherein X is N orCR^(e), R^(b), R^(c) and R^(e) are each H, R^(a) is selected from thegroup consisting of H, methyl, ethyl, methoxy, ethoxy, —CF₃, —CHF₂,—CH₂F and F; D: is selected from the group consisting of cyclopentyl,cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 2-, 3- and 4-pyridyl,whereby cyclopentyl and cyclohexyl optionally may be substituted by 1 or2 substituents, whereby said substituents may be selected independentlyof one another from the group consisting of fluorine, F₃C—, HF₂C— andFH₂C—; whereby tetrahydrofuranyl and tetrahydropyranyl optionally may besubstituted by 1 or 2 substituents, whereby said substituents may beselected independently of one another from the group consisting offluorine, F₃C—, HF₂C— and FH₂C—; whereby pyridyl optionally may besubstituted by 1, 2, 3 or 4 substituents, whereby said substituents maybe selected independently of one another from the group consisting offluorine, chlorine, bromine, NC—, F₃C—, HF₂C—, FH₂C—F₃C—CH₂—,C₁₋₆-alkyl- and C₃₋₇-cycloalkyl; m: is selected from 1 or 2; n is 0, andsalts thereof, solvates thereof and the solvates of the aforementionedsalts thereof.
 5. A compound according to claim 1, wherein m=1.
 6. Acompound according to claim 1, wherein X═N.
 7. A compound according toclaim 1, wherein X═CR^(e).
 8. A compound according to claim 1, wherein Dis either 4,4-difluorocyclohexyl, tetrahydropyran-4-yl or4-methyl-3-pyridyl, wherein none of these two groups has furthersubstituents and m=1.
 9. A compound according to claim 1, wherein thecompound is selected from the group consisting of

and pharmaceutically acceptable salts thereof.
 10. A compound accordingto claim 1, wherein the compound is selected from the group consistingof

and pharmaceutically acceptable salts thereof.
 11. A compound accordingto claim 1, wherein the compound is selected from the group consistingof a compound according to formula (Ia), formula (Ib), formula (Ic) andformula (Id)

wherein R^(a), R^(b), R^(c), R^(d), R^(e), D, m and n are as defined inclaim 1, and pharmaceutically acceptable salts thereof.
 12. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutical carrier.
 13. A pharmaceutical compositioncomprising a compound according to claim 1 and another active substance.